We have examined the interaction of human plasma high density lipoprotein (HDL) with the unesterified cholesterol-rich lipid particles that we previously isolated from human atherosclerotic lesions. We have determined if HDL can solubilize these pathologically accumulated lipid particles. We incubated purified human aortic lipid particles with HDL in a shaking water bath at 37 degrees C for 0.5 to 48 hrs. The mixtures were passed over a gel-filtration column to separate the aortic lipid particles (eluted in the void volume because of their large size, equals approximately llOO A in diameter) and HDL (eluted in the internal volume because of their small size, equals approximately 100 angstroms). The reduction of aortic lipid particle cholesterol that eluted in the void volume reached a maximum of 50% when 4 moles of HDL phospholipid per mole of aortic lipid particle phospholipid were mixed and incubated. This maximum depletion occurred by 4 hours of incubation. Low density lipoprotein did not reduce elution of aortic lipid particle cholesterol in the void volume suggesting that this lipoprotein, in contrast to HDL, could not solubilize aortic lipid particle cholesterol. The physical interaction of HDL and aortic lipid particles was assessed by electron microscopy. Normal-sized as well as apparently enlarged HDL lipoprotein particles (190-220 angstroms) were found associated with the large multilamellar aortic lipid particles. Some enlarged HDL particles formed clusters that occupied a domain similar to the size of the aortic lipid particles. Our findings suggest that HDL can solubilize cholesterol-rich lipid particles, in vitro, and may themselves become transiently enlarged during this process.